The microbiota-gut-brain axis (MGBA) has emerged as a critical frontier in understanding neurological disorders, including epilepsy. Microbial disequilibrium potentially alters brain homeostasis and could potentiate an inflammatory state linking intestinal dysbiosis and intractable seizures. The current study sought to probe the anti-kindling, electrographical, behavioral and neuropathological impacts of combined intervention of probiotics (PRO; 10 ml/kg) and pregabalin (PRG; 10 mg/kg) in PTZ-induced epileptic mice for 21 days. Adult BALB/c mice were kindled via subthreshold dose of (PTZ 40 mg/kg) until mice reached seizure stage of 4-5. After the procedure, mice were tested using a set of behavioral tests, and redox alterations along with cellular pathology were assessed. vEEG monitoring revealed that kindling instigated recurrent polyspikes of high amplitude with generalized epileptic seizures which were markedly impeded in the mice treated with dual regime suggesting potential preventive impact of probiotic therapy on neuronal hyperexcitability. Additionally, combination intervention exerted positive behavioral outcomes as it ameliorated anxiety and depressive-like phenotypes along with cognitive impairments (P < 0.05) vs. PTZ control. Moreover, probiotic and pregabalin therapy incurred gut-microbiota antioxidant neuroprotection and prevented morbid neurodegeneration as evidenced by decreased production of oxidative stressors (MDA and AchE; p < 0.01) and increase in activity of antioxidant factors (SOD; P < 0.01 and CAT; P < 0.05). Furthermore, these commensal species and PRG duo regulates inflammation and halted neuronal apoptosis in CA1 and CA3 subfields of the cornu-ammonis. Overall, our findings support probiotics as an adjuvant therapy to shift treatment paradigms in drug-resistant epilepsy by altering gut-microbiome pathological neural links.
